2,3-diaryl-pyrazolo[1,5-b]pyridazines derivatives, their preparation and their use as cyclooxygenase, 2 (COX-2) inhibitors

ABSTRACT

The invention provides a pharmaceutical composition comprising a compound of formula (I)  
                 
or a pharmaceutically acceptable salt, solvate, ester or salt or solvate of such ester, of a compound of formula (I) in which: 
         R 0  is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy substituted by one or more fluorine atoms, or O(CH 2 ) n NR 4 R 5 ;    R 1  and R 2  are independently selected from H, C 1-6 alkyl, C 1-6 alkyl substituted by one or more fluorine atoms, C 1-6 alkoxy, C 1-6 hydroxyalkyl, SC 1-6 alkyl, C(O)H, C(O)C 1-6 alkyl, C 1-6 alkylsulphonyl, C 1-6 alkoxy substituted by one or more fluorine atoms, O(CH 2 ) n CO 2 C 1-6 alkyl, O(CH 2 ) n SC 1-6 alkyl, (CH 2 ) n NR 4 R 5 , (CH 2 ) n SC 1-6 alkyl or C(O)NR 4 R 5 ; with the proviso that when R 0  is at the 4-position and is halogen, at least one of R 1  and R 2  is C 1-6 alkylsulphonyl, C 1-6 alkoxy substituted by one or more fluorine atoms, O(CH 2 ) n CO 2 C 1-6 alkyl, O(CH 2 ) n SC 1-6 alkyl, (CH 2 ) n NR 4 R 5  or (CH 2 ) n SC 1-6 alkyl, C(O)NR 4 R 5 ;    R 3  is C 1-6 alkyl or NH 2 ;    R 4  and R 5  are independently selected from H and C 1-6 alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring; and n is 1-4; and an inhibitor of the release, or action, of tumour necrosis factor α.

This invention relates to pyrazolo[1,5-b]pyridazine derivatives, toprocesses for their preparation, to pharmaceutical compositionscontaining them and to their use in medicine.

The enzyme cyclooxygenase (COX) has recently been discovered to exist intwo isoforms, COX-1 and COX-2. COX-1 corresponds to the originallyidentified constitutive enzyme while COX-2 is rapidly and readilyinducible by a number of agents including mitogens, endotoxin, hormones,cytokines and growth factors. Prostaglandins generated by the action ofCOX have both physiological and pathological roles. It is generallybelieved that COX-1 is responsible for the important physiologicalfunctions such as maintenance of gastrointestinal integrity and renalblood flow. In contrast the inducible form, COX-2, is believed to beresponsible for the pathological effects of prostaglandins where rapidinduction of the enzyme occurs in response to such agents asinflammatory agents, hormones, growth factors and cytokines. A selectiveinhibitor of COX-2 would therefore have anti-inflammatory, anti-pyreticand analgesic properties, without the potential side effects associatedwith inhibition of COX-1. We have now found a novel group of compoundswhich are both potent and selective inhibitors of COX-2.

The invention thus provides the compounds of formula (I)

and pharmaceutically acceptable derivatives thereof in which:

-   R⁰ is halogen, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one    or more fluorine atoms, or O(CH₂)_(n)NR⁴R⁵;-   R¹ and R² are independently selected from H, C₁₋₆alkyl, C₁₋₆alkyl    substituted by one or more fluorine atoms, C₁₋₆alkoxy,    C₁₋₆hydroxyalkyl, SC₁₋₆alkyl, C(O)H, C(O)C₁₋₆alkyl,    C₁₋₆alkylsulphonyl, C₁₋₆alkoxy substituted by one or more fluorine    atoms, O(CH₂)_(n)CO₂C₁₋₆alkyl, O(CH₂)_(n)SC₁₋₆alkyl, (CH₂)_(n)NR⁴R⁵,    (CH₂)_(n)SC₁₋₆alkyl or C(O)NR⁴R⁵; with the proviso that when R⁰ is    at the 4-position and is halogen, at least one of R¹ and R² is    C₁₋₆alkylsulphonyl, C₁₋₆alkoxy substituted by one or more fluorine    atoms, O(CH₂)_(n)CO₂C₁₋₆alkyl, O(CH₂)_(n)SC₁₋₆alkyl, (CH₂)_(n)NR⁴R⁵    or (CH₂)_(n)SC₁₋₆alkyl, C(O)NR⁴R⁵;-   R³ is C₁₋₆alkyl or NH₂;-   R⁴ and R⁵ are independently selected from H, or C₁₋₆alkyl or,    together with the nitrogen atom to which they are attached, form a    4-8 membered saturated ring; and-   n is 1-4.

By pharmaceutically acceptable derivative is meant any pharmaceuticallyacceptable salt, solvate or ester, or salt or solvate of such ester, ofthe compounds of formula (I), or any other compound which uponadministration to the recipient is capable of providing (directly orindirectly) a compound of formula (I) or an active metabolite or residuethereof.

It will be appreciated that, for pharmaceutical use, the salts referredto above will be the physiologically acceptable salts, but other saltsmay find use, for example in the preparation of compounds of formula (I)and the physiologically acceptable salts thereof.

Suitable pharmaceutically acceptable salts of the compounds of formula(I) include acid addition salts formed with inorganic or organic acids,preferably inorganic acids, e.g. hydrochlorides, hydrobromides andsulphates.

The term halogen is used to represent fluorine, chlorine, bromine oriodine.

The term ‘alkyl’ as a group or part of a group means a straight orbranched chain alkyl group, for example a methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl or t-butyl group.

Preferably, R⁰ is at the 3- or 4-position of the phenyl ring, as definedin formula (I).

Preferably, R⁰ is at the 6-position of the pyridazine ring, as definedin formula (I).

Preferably, R⁰ is F, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkoxy substituted byone or more fluorine atoms, or O(CH₂)₁₋₃NR⁴R⁵. More preferably R⁰ is F,C₁₋₃alkoxy or C₁₋₃alkoxy substituted by one or more fluorine atoms.

Preferably, R¹ is C₁₋₄alkylsulphonyl, C₁₋₄alkoxy substituted by one ormore fluorine atoms, O(CH₂)₁₋₃CO₂C₁₋₄alkyl, O(CH₂)₁₋₃SC₁₋₄alkyl, (CH₂)₁NR⁴R⁵, (CH₂)₁₋₃SC₁₋₄alkyl or C(O)NR⁴R⁵ or, when R⁰ is C₁₋₆alkyl,C₁₋₄alkoxy, O(CH₂)_(n)NR⁴R⁵, may also be H. More preferably R¹ isC₁₋₄alkylsulphonyl, C₁₋₄alkoxy substituted by one or more fluorine atomsor, when R⁰ is C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one ormore fluorine atoms, or O(CH₂)_(n)NR⁴R⁵, may also be H.

Preferably, R² is H.

Preferably, R³ is methyl or NH₂.

Preferably R⁴ and R⁵ are independently C₁₋₃alkyl or, together with thenitrogen atom to which they are attached, form a 5-6 membered saturatedring.

Preferably, n is 1-3, more preferably 1 or 2.

Within the invention there is provided one group of compounds of formula(I) (group A) wherein: R⁰ is F, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkoxysubstituted by one or more fluorine atoms, or O(CH₂)_(n)NR⁴R⁵; R¹ isC₁₋₄alkylsulphonyl, C₁₋₄alkoxy substituted by one or more fluorineatoms, O(CH₂)_(n)CO₂C₁₋₄alkyl, O(CH₂)_(n)SC₁₋₄alkyl, (CH₂)_(n)NR⁴R⁵,(CH₂)_(n)SC₁₋₄alkyl or C(O)NR⁴R⁵ or, when R⁰ is C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkoxy substituted by one or more fluorine atoms, orO(CH₂)_(n)NR⁴R⁵, may also be H; R² is H; R³ is methyl or NH₂; R⁴ and R⁵are independently C₁₋₃alkyl or, together with the nitrogen atom to whichthey are attached, form a 5-6 membered saturated ring; and n is 1-3.

Within group A, there is provided another group of compounds (group A1)wherein R⁰ is F, methyl, C₁₋₂alkoxy, OCHF₂, or O(CH₂)_(n)NR⁴R⁵; R¹ ismethylsulphonyl, OCHF₂, O(CH₂)_(n)CO₂C₁₋₄alkyl, O(CH₂)_(n)SCH₃,(CH₂)_(n)NR⁴R⁵, (CH₂)_(n)SCH₃ or C(O)NR⁴R⁵ or, when R⁰ is methyl,C₁₋₂alkoxy, OCHF₂, or O(CH₂)_(n)N(CH₃)₂, may also be H; R² is H; R³ ismethyl or NH₂; R⁴ and R⁵ are both methyl or, together with the nitrogenatom to which they are attached, form a 5-6 membered saturated ring; andn is 1-2.

Within group A, there is provided a further group of compounds (groupA2) wherein R⁰ is F, C₁₋₃alkoxy or C₁₋₃alkoxy substituted by one or morefluorine atoms; R¹ is C₁₋₄alkylsulphonyl, C₁₋₄alkoxy substituted by oneor more fluorine atoms or, when R⁰ C₁₋₃alkoxy or C₁₋₃alkoxy substitutedby one or more fluorine atoms, may also be H; R² is H; and R³ is methylor NH₂.

Within groups A, A1 and A2, R⁰ is preferably at the 3- or 4-position ofthe phenyl ring and R² is preferably at the 6-position of the pyridazinering.

It is to be understood that the present invention encompasses allisomers of the compounds of formula (I) and their pharmaceuticallyacceptable derivatives, including all geometric, tautomeric and opticalforms, and mixtures thereof (e.g. racemic mixtures).

Particularly preferred compounds of the invention are:

-   3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-pyrazolo[1,5-b]pyridazine;-   6-difluoromethoxy-2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;-   2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)pyrazolo[1,5-b]pyridazine;-   2-(4-fluoro-phenyl)-6-methanesulfonyl-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;-   2-(4-difluoromethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;-   4-[2-(4-ethoxy-phenyl)-pyrazolo[1,5-b]pyridazin-3-yl]-benzenesulfonamide;-   6-difluoromethoxy-2-(3-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;    and pharmaceutically acceptable derivatives thereof.

Compounds of the invention are potent and selective inhibitors of COX-2.This activity is illustrated by their ability to selectively inhibitCOX-2 over COX-1.

In view of their selective COX-2 inhibitory activity, the compounds ofthe present invention are of interest for use in human and veterinarymedicine, particularly in the treatment of the pain (both chronic andacute), fever and inflammation of a variety of conditions and diseases.Such conditions and diseases are well known in the art and includerheumatic fever; symptoms associated with influenza or other viralinfections, such as the common cold; lower back and neck pain; headache;toothache; sprains and strains; myositis; neuralgia; synovitis;arthritis, including rheumatoid arthritis; degenerative joint diseases,including osteoarthritis; gout and ankylosing spondylitis; tendinitis;bursitis; skin related conditions, such as psoriasis, eczema, burns anddermatitis; injuries, such as sports injuries and those arising fromsurgical and dental procedures.

The compounds of the invention may also be useful for the treatment ofother conditions mediated by selective inhibition of COX-2.

For example, the compounds of the invention may inhibit cellular andneoplastic transformation and metastatic tumour growth and hence beuseful in the treatment of certain cancerous diseases, such as coloniccancer.

Compounds of the invention may also prevent neuronal injury byinhibiting the generation of neuronal free radicals (and hence oxidativestress) and therefore may be of use in the treatment of stroke;epilepsy; and epileptic seizures (including grand mal, petit mal,myoclonic epilepsy and partial seizures).

Compounds of the invention also inhibit prostanoid-induced smooth musclecontraction and hence may be of use in the treatment of dysmenorrhoeaand premature labour.

Compounds of the invention inhibit inflammatory processes and thereforemay be of use in the treatment of asthma, allergic rhinitis andrespiratory distress syndrome; gastrointestinal conditions such asinflammatory bowel disease, Chron's disease, gastritis, irritable bowelsyndrome and ulcerative colitis; and the inflammation in such diseasesas vascular disease, migraine, periarteritis nodosa, thyroiditis,aplastic anemia, Hodgkin's disease, sclerodoma, type I diabetes,myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome,Bechet's syndrome, polymyositis, gingivitis, conjunctivitis andmyocardial ischemia.

Compounds of the invention may also be useful in the treatment ofophthalmic diseases such as retinitis, retinopathies, uveitis and ofacute injury to the eye tissue.

Compounds of the invention may also be useful for the treatment ofcognitive disorders such as dementia, particularly degenerative dementia(including senile dementia, Alzheimer's disease, Pick's disease,Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease),and vascular dementia (including multi-infarct dementia), as well asdementia associated with intracranial space occupying lesions, trauma,infections and related conditions (including HIV infection), metabolism,toxins, anoxia and vitamin deficiency; and mild cognitive impairmentassociated with ageing, particularly Age Associated Memory Impairment.

According to a further aspect of the invention, we provide a compound offormula (I) or a pharmaceutically acceptable derivative thereof for usein human or veterinary medicine.

According to another aspect of the invention, we provide a compound offormula (I) or a pharmaceutically acceptable derivative thereof for usein the treatment of a condition which is mediated by selectiveinhibition of COX-2.

According to a further aspect of the invention, we provide a method oftreating a human or animal subject suffering from a condition which ismediated by selective inhibition of COX-2 which comprises administeringto said subject an effective amount of a compound of formula (I) or apharmaceutically acceptable derivative.

According to another aspect of the invention, we provide the use of acompound of formula (I) or a pharmaceutically acceptable derivativethereof for the manufacture of a therapeutic agent for the treatment ofa condition which is mediated by selective inhibition of COX-2, such asan inflammatory disorder.

According to a further aspect of the invention, we provide a method oftreating a human or animal subject suffering from an inflammatorydisorder, which method comprises administering to said subject aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof.

It is to be understood that reference to treatment includes bothtreatment of established symptoms and prophylactic treatment, unlessexplicitly stated otherwise.

It will be appreciated that the compounds of the invention mayadvantageously be used in conjunction with one or more other therapeuticagents. Examples of suitable agents for adjunctive therapy include painrelievers such as a glycine antagonist, a sodium channel inhibitor (e.g.lamotrigine), a substance P antagonist (e.g. an NK₁ antagonist),acetaminophen or phenacetin; a matrix metalloproteinase inhibitor; anitric oxide synthase (NOS) inhibitor (e.g. an iNOS or an nNOSinhibitor); an inhibitor of the release, or action, of tumour necrosisfactor α; an antibody therapy (e.g. a monoclonal antibody therapy); astimulant, including caffeine; an H₂-antagonist, such as ranitidine; aproton pump inhibitor, such as omeprazole; an antacid, such as aluminiumor magnesium hydroxide; an antiflatulent, such as simethicone; adecongestant, such as phenylephrine, phenylpropanolamine,pseudoephedrine, oxymetazoline, epinephrine, naphazoline,xylometazoline, propylhexedrine, or levo-desoxyephedrine; anantitussive, such as codeine, hydrocodone, carmiphen, carbetapentane, ordextramethorphan; a diuretic; or a sedating or non-sedatingantihistamine. It is to be understood that the present invention coversthe use of a compound of formula (I) or a pharmaceutically acceptablederivative thereof in combination with one or more other therapeuticagents.

The compounds of formula (I) and their pharmaceutically acceptablederivatives are conveniently administered in the form of pharmaceuticalcompositions. Thus, in another aspect of the invention, we provide apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable derivative thereof adapted for use in humanor veterinary medicine. Such compositions may conveniently be presentedfor use in conventional manner in admixture with one or morephysiologically acceptable carriers or excipients.

The compounds of formula (I) and their pharmaceutically acceptablederivatives may be formulated for administration in any suitable manner.They may, for example, be formulated for topical administration oradministration by inhalation or, more preferably, for oral, transdermalor parenteral administration. The pharmaceutical composition may be in aform such that it can effect controlled release of the compounds offormula (I) and their pharmaceutically acceptable derivatives.

For oral administration, the pharmaceutical composition may take theform of, for example, tablets (including sub-lingual tablets), capsules,powders, solutions, syrups or suspensions prepared by conventional meanswith acceptable excipients.

For transdermal administration, the pharmaceutical composition may begiven in the form of a transdermal patch, such as a transdermaliontophoretic patch.

For parenteral administration, the pharmaceutical composition may begiven as an injection or a continuous infusion (e.g. intravenously,intravascularly or subcutaneously). The compositions may take such formsas suspensions, solutions or emulsions in oily or aqueous vehicles andmay contain formulatory agents such as suspending, stabilising and/ordispersing agents. For administration by injection these may take theform of a unit dose presentation or as a multidose presentationpreferably with an added preservative.

Alternatively for parenteral administration the active ingredient may bein powder form for reconstitution with a suitable vehicle.

The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

As stated above, the compounds of the invention may also be used incombination with other therapeutic agents. The invention thus provides,in a further aspect, a combination comprising a compound of formula (I)or a pharmaceutically acceptable derivative thereof together with afurther therapeutic agent.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art.

A proposed daily dosage of a compound of formula (I) for the treatmentof man is 0.01 mg/kg to 500 mg/kg, such as 0.05 mg/kg to 100 mg/kg, e.g.0.1 mg/kg to 50 mg/kg, which may be conveniently administered in 1 to 4doses. The precise dose employed will depend on the age and condition ofthe patient and on the route of administration. Thus, for example, adaily dose of 0.25 mg/kg to 10 mg/kg may be suitable for systemicadministration.

Compounds of formula (I) and pharmaceutically acceptable derivativesthereof may be prepared by any method known in the art for thepreparation of compounds of analogous structure.

Suitable methods for the preparation of compounds of formula (I) andpharmaceutically acceptable derivatives thereof are described below. Inthe formulae that follow R⁰ to R⁵ and n are as defined in formula (I)above unless otherwise stated; Hal is a halogen, such as Br or I; X⁻ isa counterion, such as I⁻; and alkyl is as previously defined.

Thus according to a first process (A), compounds of formula (I) may beprepared by reacting a compound of formula (II)

or a protected derivative thereof with a boronic acid of formula (III)

or a suitable derivative thereof in the presence of a suitabletransition metal catalyst. Suitable derivatives of formula (III) includeboronic acid esters, such as those described in R. Miyaura et al, J.Org. Chem., 1995, 60, 7508-7510. Conveniently, the reaction is carriedout in a solvent, such as an ether (e.g. 1,2 dimethoxyethane); in thepresence of a base, such as an inorganic base (e.g. sodium carbonate);and employing a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0).

According to a another process (B), compounds of formula (I) wherein R³is C₁₋₆alkyl may be prepared by oxidising a compound of formula (IV)

or a protected derivative thereof under conventional conditions.Conveniently the oxidation is effected using a monopersulfate compound,such as potassium peroxymonosulfate (known as Oxone™) and the reactionis carried out in a solvent, such as an aqueous alcohol, (e.g. aqueousmethanol), and at between −78° C. and ambient temperature.

According to a another process (C), compounds of formula (I) wherein R¹is C₁₋₆alkylsulphonyl may be prepared by oxidising a compound of formula(V)

or a protected derivative thereof under conventional conditions.Conveniently the oxidation is effected in the manner described justabove for process (B).

According to a another process (D), compounds of formula (I) wherein R¹is C₁₋₆alkoxy substituted by one or more fluorine atoms may be preparedby reacting an alcohol of formula (VI)

or a protected derivative thereof with a halofluoroalkane underconventional conditions. Conveniently the reaction is effected in asolvent, such as a polar solvent (e.g. N,N-dimethylformamide), in thepresence of a strong base, such as an inorganic hydride (e.g. sodiumhydride), at about ambient temperature and using the appropriatebromofluoroalkane to give the desired compound of formula (I).

According to another process (E) compounds of formula (I) may beprepared by interconversion, utilising other compounds of formula (I) asprecursors. The following procedures are illustrative of suitableinterconversions.

Compounds of formula (I) wherein R¹ or R² represent C₁₋₄alkylsubstituted by one or more fluorine atoms may be prepared from theappropriate compound of formula (I) wherein R¹ or R² isC₁₋₆hydroxyalkyl, C(O)H or C(O)C₁₋₆alkyl, by treatment with a suitablesource of fluorine. Suitable sources of fluorine include, for example,diethylaminosulphur trifluoride. Conveniently the reaction is effectedin the presence of a solvent, such as a halogenated hydrocarbon (e.g.dichloromethane), and at reduced temperature, such as −78° C.

Compounds of formula (I) wherein R¹ or R² represent C(O)H may beprepared from the corresponding compound of formula (I) wherein R¹ or R²represent CH₂OH by oxidation. Suitable oxidising agents include, forexample, manganese (IV) oxide. Conveniently the oxidation is effected inthe presence of a solvent, such as a halogenated hydrocarbon (e.g.chloroform), and at elevated temperature (e.g. reflux).

Compounds of formula (I) wherein R¹ or R² represent C₁₋₆hydroxyalkyl,and wherein the hydroxy group is attached to the carbon linked to thepyridazine ring, may be prepared by reduction of the compound of formula(I) wherein R¹ or R² represent the corresponding aldehyde or ketone.Suitable reducing agents include hydride reducing agents, such asdiisobutylaluminium hydride.

Conveniently the reduction is effected in the presence of a solvent,such as a halogenated hydrocarbon (e.g. dichloromethane), and at reducedtemperature, such as −78° C.

As will be appreciated by those skilled in the art it may be necessaryor desirable at any stage in the synthesis of compounds of formula (I)to protect one or more sensitive groups in the molecule so as to preventundesirable side reactions.

Another process (F) for preparing compounds of formula (I) thuscomprises deprotecting protected derivatives of compounds of formula(I).

The protecting groups used in the preparation of compounds of formula(I) may be used in conventional manner. See, for example, thosedescribed in ‘Protective Groups in Organic Synthesis’ by Theodora W.Greene and Peter G. M. Wuts, second edition, (John Wiley and Sons,1991), which also describes methods for the removal of such groups.

Compounds of formula (II) may be prepared by halogenating compounds offormula (VII)

by conventional means.

Thus esters of formula (VI) are first hydrolysed to their correspondingacids, for example by treatment with a strong base (e.g. sodiumhydroxide), in the present of a solvent (e.g. ethanol) and at elevatedtemperature. The corresponding acid is then treated with a halogenatingagent, conveniently at ambient temperature and in a solvent (e.g.chlorinated hydrocarbon), under which conditions the acid undergoes bothhalogenation and decarboxylation. Conveniently, the halogenating agentis a brominating agent, such as bromine in the presence of a strong acid(e.g. hydrobromic acid in acetic acid) or N-bromosuccinimide, to yieldthe corresponding compound of formula (II) wherein Hal is bromine.

Esters of formula (VII) may be prepared by reacting a compound offormula (VIII)

with an aminopyridazinium complex of formula (IX)

under conventional conditions. Conveniently the reaction is effected inthe presence of a base, such as potassium carbonate, a solvent, such asN,N-dimethylformamide and at ambient temperature.

Boronic acids of formula (III) are either known compounds or may beprepared by literature methods such as those described in, for example,EPA publication No. 533268.

Compounds of formulae (IV), (V) and (VI) may be prepared by methodsanalogous to those described for the preparation of the compound offormula (I) from compounds of formula (II).

Compounds of formula (VIII) are either known compounds or may beprepared by literature methods such as those described in, for example,D H Wadsworth et al, J Org Chem, (1987), 52(16), 3662-8 and J. Morrisand D. G. Wishka, Synthesis (1994), (1), 43-6.

Compounds of formula (IX) are either known compounds or may be preparedby literature methods such as those described in, for example, YKobayashi et al., Chem Pharm Bull, (1971), 19(10), 2106-15; T. Tsuchiya,J. Kurita and K. Takayama, Chem. Pharm. Bull. 28(9) 2676-2681 (1980) andK Novitskii et al., Khim Geterotskil Soedin, 1970 2, 57-62.

Certain intermediates described above are novel compounds, and it is tobe understood that all novel intermediates herein form further aspectsof the present invention. Compounds of formula (II) are keyintermediates and represent a particular aspect of the presentinvention.

Conveniently, compounds of the invention are isolated following work-upin the form of the free base. Pharmaceutically acceptable acid additionsalts of the compounds of the invention may be prepared usingconventional means.

Solvates (e.g. hydrates) of a compound of the invention may be formedduring the work-up procedure of one of the aforementioned process steps.

The following Examples illustrate the invention but do not limit theinvention in any way. All temperatures are in ° C. Flash columnchromatography was carried out using Merck 9385 silica. Thin layerchromatography (Tlc) was carried out on silica plates. NMR was carriedout on a Brucker 250 MHz spectrometer. Chemical shifts are given, withrespect to tetramethylsilane as internal chemical shift reference, in δppm. The following abbreviations are used: Me=methyl, s=singlet,d=doublet, t=triplet and m=multiplet.

EXAMPLE 16-Difluoromethoxy-2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine(i) 6-Methoxy-2-(4-fluoro-phenyl-pyrazolo[1,5-b]pyridazine-3-carboxylicAcid Methyl Ester

1,8-Diazabicyclo[5.4.0]undec-7-ene (3.39 ml) was added to a mixture of3-(4-fluorophenyl)-prop-2-ynoic acid methyl ester (3.36 g) and1-amino-3-methoxy-pyridazin-1-ium mesitylene sulphonate¹ (6.1419 g) inacetonitrile (125 ml) and the mixture was stirred at ambient temperaturefor 48 hours. During the first 2 hours a stream of air was passedthrough the reaction. The mixture was concentrated in vacuo, dissolvedin ethyl acetate (150 ml), washed with water (3×25 ml), dried (MgSO₄),filtered and evaporated in vacuo to give the title compound as a brownsolid (4.77 g).

¹H NMR (CDCl₃): 8.4 (d, 1H, J=10 Hz) 7.85-7.90 (m, 2H) 7.1-7.2 (m, 2H)6.9-7.0 (d, 1H, J=10 Hz) 4.1 (s, 3H) 3.9 (s, 3H)

MH⁺ 302

Ref:¹ T. Tsuchiya, J. Kurita and K. Takayama, Chem. Pharm. Bull. 28(9)2676-2681 (1980).

(ii) 6-Methoxy-2-(4-fluoro-phenyl-pyrazolo[1,5-b]pyridazine-3-carboxylicAcid

A mixture of6-methoxy-2-(4-fluoro-phenyl-pyrazolo[1,5-b]pyridazine-3-carboxylic acidmethyl ester (4.469 g), 2N sodium hydroxide (50 ml) and methanol (90 ml)was heated at reflux for 2 hours. The cooled solution was added to 2Nhydrochloric acid (200 ml) and the title compound was isolated byfiltration as a beige solid (3.639 g).

¹H NMR (DMSO-d₆): 12.8 (br. s, 1H) 8.4 (d, 1H, J=10 Hz) 7.8-7.9 (m, 2H)7.21-7.32 (m, 2H) 7.15-7.2 (d, 1H, J=10 Hz) 4.0 (s, 3H)

MH⁺ 288

(iii)2-(4-Fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine

A mixture of6-methoxy-2-(4-fluoro-phenyl-pyrazolo[1,5-b]pyridazine-3-carboxylic acid(869 mg) and sodium bicarbonate (756 mg) in dimethylformamide (10 ml)was treated with N-bromosuccinimide (587 mg) and stirred at ambienttemperature for 1 hour, then added to water (50 ml) and extracted withethyl acetate (3×50 ml), dried (MgSO₄), and evaporated in vacuo. Theresulting brown solid (1.612 g) was dissolved in 1,2 dimethoxyethane (20ml). 2N Aqueous sodium carbonate solution (10 ml) was added togetherwith 4-(methanesulphonyl)phenyl boronic acid (660 mg) andtetrakis(triphenylphosphine)palladium (0) (100 mg) and the mixture washeated at reflux for 20 hours. The reaction was poured into water (50ml), extracted with dichloromethane (3×100 ml). The combined organicextracts were dried (MgSO₄) and evaporated in vacuo to give a brownsolid (1.116 g) which was purified by flash column chromatography onsilica, eluting with cyclohexane/ethyl acetate (4:1 then 2:1), to givethe title compound as a yellow solid (390 mg).

Tic, SiO₂, R_(f) 0.3 (1:1 cyclohexane/ethyl acetate), detection UV

MH⁺ 398

(iv)2-(4-Fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-6-ol

A mixture of2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine(321 mg) and pyridine hydrochloride (1.4 g) was heated to and at 200° C.in a sealed vessel (Reactivial™) for 3 hours. The cooled reaction waspoured into water (20 ml), and extracted with ethyl acetate (3×30 ml).The combined organic extracts dried (MgSO₄), filtered and evaporated invacuo to give a solid which was triturated with diethyl ether to givethe title compound as a beige solid (119 mg).

Tlc, SiO₂, R_(f) 0.07 (1:2 cyclohexane/ethyl acetate), detection UV.

MH⁺ 384

(v)6-Difluoromethoxy-2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine

A solution of2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-6-ol(0.2 g) in anhydrous dimethyl formamide (5 ml) was treated with sodiumhydride (0.046 g, 60% dispersion in mineral oil), after effervescenceceased a stream of bromodifluoromethane gas was passed through themixture at ambient temperature for 30 minutes. The reaction mixture wasthen poured into water (50 ml) and extracted with ethyl acetate (50 ml),the organic extract was washed with water (3×50 ml), dried andconcentrated in vacuo. The residue was purified by chromatography togive the title compound as a white solid (0.17 g).

MH⁺ =434

¹HNMR(CDCl₃):δ8.05-8.0(d,J=10 HZ,2H) 8.0-7.95(d,J=10 HZ,1H)7.6-7.5(m,4H) 7.8-7.2(t,J=70 HZ,1H) 7.1-7.05(t,J=11 HZ,2H)6.9-6.85(d,J=10 HZ,1H) 3.15(s,3H)

Tlc, SiO₂, R_(f) 0.35(ethyl acetate/cyclohexane(1/1))

EXAMPLE 23-(4-Methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-pyrazolo[1,5-b]pyridazine(i) 2-(4-Methoxy-phenyl)-pyrazolo[1,5-b]pyridazine-3-carboxylic AcidMethyl Ester

Diazabicyclo[5.4.0]undec-7-ene (22.76 ml, 2 eq) was added dropwise to asolution of methyl 3-(4-methoxy-phenyl)-prop-2-ynoic acid¹ (14.46 g, 76mM) and 1-amino pyridazinium iodide² (2 eq) in acetonitrile undernitrogen and stirred for 6 h. Purification by chromatography on silicagel eluting with toluene, then toluene:ethyl acetate (9:1) gave thetitle compound (2.76 g) as a brown solid.

MH⁺ 284

1H NMR (CDCl₃) δ 3.87 (3H, s) 3.9 (3H, s) 7.0 (2H, d, J=9 Hz) 7.25 (1H,dd, J=9 & 4 Hz) 7.90 (2H, d, J=9 Hz) 8.45 (1H, dd, J=4 & 2 Hz) 8.55 (1H,dd, J=9 & 2 Hz)

Ref: ¹ J. Morris and D. G. Wishka, Synthesis (1994), (1), 43-6

Ref: ² Kobayashi et al Chem.Pharm.Bull. (1971), 19 (10), 2106-15

(ii)3-(4-Methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-pyrazolo[1,5-b]pyridazine

A mixture of 2-(4-methoxy-phenyl)-pyrazolo[1,5-b]pyridazine-3-carboxylicacid methyl ester (2.76 g) and aq. sodium hydroxide (2N, 30 ml) inethanol (30 ml) was refluxed under nitrogen for 2 h. The cooled mixturewas acidified with hydrochloric acid (2N) and the resulting white solid(2.53 g) isolated by filtration. This solid was dissolved in DMF andsodium bicarbonate (2.67 g, 3.3 eq) added, followed byN-bromosuccinimide (1.88 g, 1.1 eq) portionwise. After stirring for 1 hunder nitrogen, water was added and extracted into ethyl acetate (2×25ml). The dried organic phase was concentrated and the residue taken upin DME (60 ml). Aqueous sodium carbonate (2N, 15 ml) was added, followedby 4-methanesulfonyl-phenylboronic acid (3.12 g) andtetrakis(triphenylphosphine)palladium(0) (250 mg). The mixture washeated at reflux under nitrogen for 18 h, cooled, poured into water andextracted into ethyl acetate (2×25 ml). The combined organic phases weredried and concentrated onto silica gel. Chromatography on silica geleluting with toluene:ethyl acetate (8:1) gave, on concentration, thetitle compound (3.58 g) as a cream solid.

MH⁺ 380

1H NMR (DMSO) δ 3.25 (3H, s) 3.75 (3H, s) 6.95 (2H, d, J=8.5 Hz) 7.25(1H, dd, J=9 & 5 Hz) 7.45 (2H, d, J=8.5 Hz) 7.60 (2H, d, J=8 Hz) 7.9(2H, d, J=8.5 Hz) 8.15 (1H, dd, J=9&2 Hz) 8.49 (1H, dd, J=5&2 Hz)

EXAMPLE 32-(4-Ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine(i)4-[3-(4-Methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-2-yl]-phenol

Boron tribromide (1 M solution in CH₂Cl₂, 2.1 eq) was added to3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-pyrazolo[1,5-b]pyridazine(3.58 g) in CH₂Cl₂ at −70°. The mixture was stirred for 10 min thenwarmed to 0° and stirred at 0° overnight. The reaction mixture was madealkaline with potassium carbonate then acidified with hydrochloric acid(2M), poured into water and extracted into CH₂Cl₂. The organic phase wasdried, filtered and concentrated to give the title compound (1.87 g) asa yellow solid.

MH⁺ 366

1H NMR (DMSO) δ 3.30 (3H, s) 6.80 (2H, d, J=8.5 Hz) 7.30 (1H, dd, J=9 &5 Hz) 7.35 (2H, d, J=8.5 Hz) 7.60 (2H, d, J=8 Hz) 8.0 (2H, d, J=8.5 Hz)8.20 (1H, dd, J=9& 2 Hz) 8.55 (1H, dd, J=5& 2 Hz) 9.75 (1H, s)

(ii)2-(4-Ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine

4-[3-(4-Methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-2-yl]-phenol(663 mg, 1.82), iodoethane (1 eq) and potassium carbonate (2 eq) inacetonitrile (30 ml) were heated at reflux under nitrogen for 18 h. Thecooled reaction mixture was partitioned between water (30 ml) and ethylacetate (30 ml). The organic phase was collected, dried and purified bychromatography to give the title compound (547 mg) as a cream foam.

MH⁺ 394

1H NMR (DMSO) δ 1.45 (3H, t, J=7 Hz) 3.10 (3H, s) 4.1 (2H, q, J=7 Hz)6.87 (2H, d, J=9 Hz) 7.08 (1H, dd, J=9 & 5 Hz) 7.55 (4H, t, J=9 Hz) 7.92(1H, dd, J=9 &2 Hz) 7.95 (2H, d, J=9 Hz) 8.20 (1H, dd, J=9& 2 Hz) 8.32(1H, dd, J=5& 2 Hz)

EXAMPLE 42-(4-Fluoro-phenyl)-6-methanesulfonyl-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine(i)2-(4-Fluoro-phenyl)-6-methylsulfanyl-pyrazolo[1,5-b]pyridazine-3-carboxylicAcid Methyl Ester

Solid t-butoxycarbonyl-O-mesitylenesulfonylhydroxylamine¹ (7.8 g) wasadded portionwise with stirring to TFA (25 ml) over 10 min then stirredfor a further 20 minutes. The solution was poured onto ice (˜200 ml) andleft until the ice melted. The resulting white solid was filtered off,washed with water, and dissolved in DME (100 ml). The solution was driedover 4 A mol. sieves for 1.5 hours, filtered then added to a solution of3-methylthio-pyridazine² (2.6 g) in dichloromethane (35 ml) and thereaction stirred at room temperature for 20 h. The intermediate salt wasisolated by filtration as light brown crystals (3.87 g), suspended inacetonitrile (100 ml) and methyl 3-(4-fluoro-phenyl)-prop-2-ynoic acid(2.02 g) added. 1,8-Diazabicyclo[5.4.0]undec-7-ene (2.1 ml) was addeddropwise and the reaction was stirred at room temperature for 20 hours.The resulting crystalline precipitate was filtered off, washed and dried(770 mg). Concentration of the filtrate gave a second crop (430 mg). Theresidues were partioned between water and ethyl acetate (100 ml each)and the aqueous layer was extracted with ethyl acetate (20 ml). Thecombined organics were washed with water, brine and dried. Removal ofsolvent gave a brown oil which was purified by flash chromatography onsilica (300 g) eluting with cyclohexane/ethyl acetate (3:1) to give afurther quantity of product (247 mg). The three crops were combined togive the title compound (1.45 g) as a light brown solid.

MH⁺ 318

1H NMR (CDCl₃) δ 2.70 (3H, s), 3.88 (3H, s) 7.08-7.18 (3H, m) 7.84 (2H,m) 8.31 (1H, d, J=10 Hz)

Ref: ¹ K Novitskii et al, Khim Geterotskil Soedin, 1970 2, 57-62

Ref: ² Barlin G. B., Brown, W. V., J Chem Soc (1968), (12), 1435-45

(ii)2-(4-Fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-6-methylsulfanyl-pyrazolo[1,5-b]pyridazine

A mixture of the2-(4-fluoro-phenyl)-6-(methylthio)-pyrazolo[1,5-b]pyridazine-3-carboxylicacid methyl ester (1.45 g) potassium carbonate (690 mg) in methanol (40ml) and water (14 ml) was stirred and heated under reflux for 20 hoursunder nitrogen. The solvents were removed and the resulting solidpartioned between ethyl acetate (50 ml) and water (250 ml). The aqueouslayer was acidified to pH1 (2 MHCl) and a solid was filtered off (1.0 g,MH⁺ 304). A mixture of the solid (1.0 g), sodium bicarbonate (557 mg)and NBS (594 mg) were stirred at room temperature for 4 hours. Thereaction was poured into water (150 ml) and extracted with ethyl acetate(3×50 ml). The combined extracts were washed with water (50 ml), brine(20 ml), dried and concentrated. The resulting solid (1.015 g, MH⁺338,340), 4-(methanesulphonyl)phenyl boronic acid (902 mg), sodiumcarbonate (740 mg) and tetrakis(triphenylphosphine)palladium(0) (175 mg)were stirred and heated under nitrogen at reflux in DME (30 mls) andwater (15 ml) for 48 hours. The reaction was poured into water andextracted with ethyl acetate (3×50 ml). The combined extracts were driedand the solvent removed to give a brown solid. This was purified onsilica (300 g) eluting with cyclohexane, ethyl acetate (1:1) to give thetitle compound (0.713 g) as a yellow solid.

MH⁺ 414

1H NMR δ (DMSO) 2.65 (3H, s) 3.28 (3H, s) 7.20-7.30 (3H, m) 7.55 (2H, m)7.62 (4H, d, J=8.5 Hz) 7.95-8.05 (3H, m)

(iii)2-(4-Fluoro-phenyl)-6-methanesulfonyl-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine

A suspension of2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-6-(methylthio)-pyrazolo[1,5-b]pyridazine(60 mg 0.145) in MeOH (5 ml) and water (2 ml) was stirred with oxone(196 mg 0.32) for 20 hours. The resulting solution was poured into water(50 ml) and extracted with chloroform (3×20 ml). The combined extractswere dried and the solvent removed. Crystallisation of the residue frommethanol gave the title compound (60 mg) as a white solid.

MH⁺ 446

1H NMR (DMSO-d₆) δ 3.34 (3H, s) 3.53 (3H, s) 7.33 (2H, t, J=9 Hz) 7.62(2H, m) 7.68 (1H, d, J=8.5 Hz) 8.04 (1H, d, J=10 Hz) 8.52 (1H, d, J=9Hz)

TLC SiO₂ Hexane:Ethyl acetate (1:1) R_(f) 0.24 UV

EXAMPLE 52-(4-Difluoromethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine

Sodium hydride (48 mg, 60% disp. in oil, 1.2 mmol) was added to asolution of4-[3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-2-yl]-phenol(200 mg, 0.55 mmol) in anhydrous dimethylformamide (5 ml).Bromodifluoromethane gas was gently bubbled through the solution for 20min, then diluted with CH₂Cl₂ (30 ml). Aqueous workup followed bychromatography on silica gel with CH₂Cl₂:ethyl acetate (3:1) as eluantthen chromatography with CH₂Cl₂:ethyl acetate (10:1) as eluant gave thetitle compound (63 mg, 28%) as a white solid.

MH⁺ 416

NMR (CDCl₃) δ8.38 (1H,dd, J=4 Hz), 8.01 (2H, d, J=8.5 Hz), 7.94 (1H, dd,J=9 & 2 Hz), 7.65 (2H, d, J=8.5 Hz) 7.57 (2H, d, J=8 Hz), 7.10 (3H, m),6.87-6.27 (1H, t, J=7.4 Hz) 3.15 (3H, s)

EXAMPLE 64-[2-(4-Ethoxy-phenyl)-pyrazolo[1,5-b]pyridazin-3-yl]-benzenesulfonamide(i) 2-(4-Ethoxy-phenyl)-pyrazolo[1,5-b]pyridazine-3-carboxylic AcidMethyl Ester

Diazabicyclo[5.4.0]undec-7-ene (1.47 ml, 2 eq) was added dropwise to asolution of methyl 3-(4-ethoxy-phenyl)-prop-2-ynoic acid (1.0 g) and1-amino pyridazinium iodide² (2.19 g) in acetonitrile (10 ml) undernitrogen and stirred for 5 h. Concentration and aqueous workup gave thetitle compound (1.2 g) as a sticky brown solid.

MH⁺ 298

(ii) 2-(4-Ethoxy-phenyl)-pyrazolo[1,5-b]pyridazine-3-carboxylic Acid

A mixture of 2-(4-ethoxy-phenyl)-pyrazolo[1,5-b]pyridazine-3-carboxylicacid methyl ester (1.2 g), ethanol (10 ml) and 2N sodium hydroxide (10ml) was heated to 800 for 1.5 h. The mixture was allowed to cool andacidified to pH 1 with 2N hydrochloric acid. The title compound wasisolated by filtration as a brown solid (716 mg, 63%).

MH⁺ 284

(iii) 2-(4-Ethoxy-phenyl)-3-iodo-pyrazolo[1,5-b]pyridazine

A mixture of 2-(4-ethoxy-phenyl)-pyrazolo[1,5-b]pyridazine-3-carboxylicacid (710 mg), N-iodosuccinimide (678 mg) and sodium bicarbonate (717mg) in DMF (8 ml) was stirred for 4 h. A further quantity ofN-iodosuccinimide(100 mg) was added and stirring continued for 2 h.Aqueous workup gave a dark brown solid which was purified by SPE withdichloromethane as eluant. This gave the title compound as anorange-brown solid (429 mg, 47%).

MH⁺ 366

(iv)4-[2-(4-Ethoxy-phenyl)-pyrazolo[1,5-b]pyridazin-3-yl]-benzenesulfonamide

A mixture of 4-iodobenzenesulphonamide (0.311 g), dipinacoldiborane¹(0.279 g), potassium acetate (486 mg) and[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) chloride complexwith dichloromethane (1:1) (0.45 g) in dimethylformamide (8 ml) washeated under nitrogen at 800 for 2 h. The cooled reaction mixture wasconcentrated in vacuo and the residue suspended in 1,2 dimethoxyethane(10 ml), 2-(4-ethoxy-phenyl)-3-iodo-pyrazolo[1,5-b]pyridazine (0.4 g)was added together with 2N sodium carbonate (4 ml) andtetrakis(triphenylphosphine)palladium (0) (20 mg) and the mixture heatedat reflux under nitrogen for 18 hours. The cooled reaction mixture waspoured into water (60 ml) and the suspension extracted with ethylacetate (3×60 ml). The organic extracts were combined, dried (Na₂SO₄)and concentrated. The residue was purified by chromatography elutingwith dichloromethane/ethyl acetate (3:1) to give the title compound as ayellow solid (0.116 g, 27%).

MH⁺ 395

NMR (CDCL₃) δ 8.32 (1H, dd, J=4 & 2 Hz), 7.97 (2H, d, J=8 Hz), 7.89 (1H,dd, J=9 & 2 Hz), 7.54 (4H, m), 7.04 (1H, dd, J=9 & 4 Hz), 6.88 (2H, d,J=9 Hz), 1.43 (3H, t, J=7 Hz)

Ref: 1 R. Miyaura et al J.Org.Chem., 1995,60,7508-7510.

EXAMPLE 76-Difluoromethoxy-2-(3-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine(i) 1-(2,2-Dibromo-vinyl)-3-fluoro-benzene

To a stirred cooled (ice/salt, 0°) solution of carbon tetrabromide(48.82 g) in anhydrous CH₂Cl₂ (200 ml) was added portionwise over 3minutes, triphenylphosphine (77.1 g), maintaining the temperature below100. The resulting orange suspension was stirred at 0° for 1 hour beforeadding to it, 3-fluorobenzaldehyde (7.8 ml). After the addition wascomplete, the suspension was stirred at 0° for 1 hour then quenched bythe addition of water (75 ml). The organic phase was separated andwashed with brine (75 ml), dried (Na₂SO₄) and evaporated to dryness. Theresidual gum was poured into cyclohexane (1 L) and stirred for 30minutes. The organic phase was decanted and the residue taken up intoCH₂Cl₂ and poured into cyclohexane (1 L). This procedure was repeatedtwice more and the combined organic phases concentrated to ˜100 ml andpassed through silica gel. The filtrate was concentrated to give thetitle compound as a mobile yellow oil (24 g, 100%).

MH⁺ 280, MH⁻ 279

NMR (CDCl₃) δ 7.05 (1H, tm, J=9 Hz) 7.3 (3H, m) 7.45 (1H, s)

(ii) (3-Fluoro-phenyl)-propynoic Acid Methyl Ester

To a stirred solution of 1-(2,2-dibromo-vinyl)-3-fluoro-benzene (23.8 g)in anhydrous THF (350 ml) cooled to −780 was added dropwise over 30minutes, n-butyllithium (2.2 eq, 1.6M in hexanes). The mixture wasstirred for a further 30 minutes at −780 before methyl chloroformate(11.6 g, 9.5 ml) was added and the resultant mixture allowed to warm to0° for 1 hour before being diluted with 1:1 saturated aqueous sodiumbicarbonate:ammonium chloride (100 ml) and extracted into ether (2×100ml). The combined organic extract was washed with brine (25 ml), dried(Na₂SO₄) and evaporated to dryness to give the title compound as a brownoil (16.7 g, 100%).

MH⁻ 173

NMR (CDCl₃) δ 7.4-7.1 (4H, m) 3.85 (3H, s, CO₂Me)

(iii)2-(3-Fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine-3-carboxylicAcid Methyl Ester

1,8-Diazabicyclo[5.4.0]undec-7-ene (5 ml) was added to a stirred,chilled, mixture of (3-fluoro-phenyl)-propynoic acid methyl ester (2.67g) and 1-amino-3-methoxy-pyridazin-1-ium mesitylene sulphonate (4.89 g)in acetonitrile (80 ml) and the mixture was stirred at 0° for 1 hourthen at ambient temperature for 18 hours. The mixture was concentratedin vacuo, and partitioned between ethyl acetate (150 ml) and water (150ml). The aqueous phase was separated and further extracted with ethylacetate (2×100 ml). The combined organic extracts were washed with water(2×50 ml), brine (25 ml), dried (MgSO₄), filtered and evaporated invacuo to give a solid which was triturated with anhydrous ether:petroleum ether (1:0.5) to give the title compound as a brown solid (2.4g, 53%).

MH⁺ 302

1H NMR (CDCl₃) δ 12.8 (1H, br s); 8.4 (1H, d, J=10 Hz) 7.7-7.6 (2H, m)7.42 (1H, q, J=8 Hz) 7.15 (1H, td, J 8 & 3 Hz) 6.95 (1H, d, J=10 Hz) 4.1(3H, s) 3.88 (3H, s)

(iv)2-(3-Fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine-3-carboxylicAcid

2N sodium hydroxide (50 ml) was added to a solution of2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine-3-carboxylicacid methyl ester (2.3 g) in absolute ethanol (50 ml) and the resultingmixture heated to reflux for three hours. The cooled reaction mixturewas poured slowly into a stirred solution of 2N hydrochloric acid (300ml). The resulting suspension was stirred at ambient temperature for 1hour then filtered and the filter cake washed with water and dried invacuo at 60° to give the title compound as an off-white solid (2.0 g,91%).

MH⁺ 288

1H NMR (DMSO) δ 8.45 (1H, d, J=10 Hz); 7.67 (2H, m); 7.5 (1H, q, J=7Hz); 7.3 (1H, td, J 7& 2 Hz); 7.21 (1H, d, J=10 Hz); 4.0 (3H, s)

(v) 3-Bromo-2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine

To a stirred solution of2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine-3-carboxylicacid (2.0 g) in anhydrous DMF (20 ml) was added n-bromosuccinimide (1.78g) and the resulting solution stirred at ambient temperature for 3hours. The reaction mixture was diluted with ethyl acetate (800 ml) andwashed sequentially with water (10×100 ml) and sat. brine (25 ml), dried(Na₂SO₄), and concentrated to give the title compound as a buff solid(2.1 g, 93%).

MH⁺ 323, MH⁻ 321

1H NMR (CDCl₃) 7.9 (2H, m) 7.8 (1H, d, J=10 Hz); 7.45 (1H, m); 7.1 91H,td, J 8 & 2 Hz); 6.78 (1H, d, J=10 Hz); 4.1 (3H, s)

(vi) 6-Difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine

Portions of3-bromo-2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine (400 mg,2.1 g total) were placed in individual Reactivials equipped with amagnetic stirrer bar. Pyridine hydrochloride (10 eq) was added to eachvial, the vials sealed, and heated to 2000 for 3 hours. The vials wereallowed to cool to ˜140° before opening and the contents poured intoice/water. The resulting mixture was extracted into ethyl acetate (3×100ml) and the combined organic extracts washed with water (7×75 ml), dried(Na₂SO₄) and evaporated to give the des-bromo phenol as a brown solid(1.0 g, MH⁺ 230). This solid was dissolved in anhydrous DMF (10 ml) andsodium hydride (60% dispersion in mineral oil, 200 mg) addedportionwise. After stirring for 20 minutes at ambient temperature thesolution was transferred to a small cooled autoclave andbromodifluoromethane (5 ml, xs, condensed at −30°) added. The autoclavewas then sealed, allowed to warm to ambient temperature and stirred for36 hours. The resulting solution was diluted with ethyl acetate (200ml), washed with water (10×20 ml), dried (Na₂SO₄), concentrated and theresidual gum purified by flash column chromatography withcyclohexane:ethyl acetate (4:1) as eluant. This gave the title compoundas a solid (652 mg, 60%).

MH⁺ 280 MH⁻ 278

NMR (DMSO) δ 8.42(1H, d, J=10 Hz) 7.85 (1H, d, J=8 Hz) 7.78 (1H, t, J=70Hz) 7.55 (1H, q, J=8 Hz) 7.38 (1H, s) 7.25 (1H, m) 7.17 (1H, d, J=10 Hz)

(vii)3-Bromo-6-difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine

N-bromo succinimide (195 mg) was added to a solution of6-difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine (251 mg)and sodium bicarbonate (185 mg) in anhydrous DMF (10 ml) and stirred for18 h. The reaction mixture was diluted with ethyl acetate (300 ml) andwashed with water (10×20 ml), brine (20 ml), dried (Na₂SO₄) andconcentrated to give the title compound as a solid (293 mg, 91%).

MH⁺ 359, MH⁻ 356/357

NMR (DMSO) δ 8.36 (1H, d, J=10 Hz) 7.88 (1H, d, J=8 Hz) 7.78 (1H, t,J=70 Hz, OCHF₂) 7.77 (1H, dm, J=10 Hz) 7.62 (1H, dt, J 8 & 6 Hz) 7.38(1H, dt, J 9 & 2 Hz) 7.3 (1H, d, J=10 Hz)

(viii)6-Difluoromethoxy-2-(3-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine

To a stirred solution of3-bromo-6-difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine(286 mg) in DMF(20 ml) was added 2N aq sodium carbonate (10 ml). To thismixture was added 4-methanesulfonyl-phenylboronic acid (180 mg) andtetrakis triphenylphosphine palladium (0) (34 mg). The resulting mixturewas stirred and heated to reflux for 18 hours. The cooled reactionmixture was diluted with ethyl acetate (300 ml) and the organic solutionwashed with water (10×30 ml) and brine (30 ml), dried (Na₂SO₄) andevaporated to give a gum which was purified by flash columnchromatography with chloroform:ethyl acetate (50:1 to 5:1) as eluant.Combination of appropriate fractions and concentration gave the titlecompound as an off-white solid (132 mg, 37%).

MH⁺ 434

1H NMR(CDCl₃) δ 8.02 (1H, d, J=9 Hz); 7.95 (2H, d, J=10 Hz); 7.58 (1H,d, 9 Hz); 7.52 (1H, t, J=70 Hz); 7.32 (3H, m); 7.08 (1H, m); 6.9 (1H, d,J=9 Hz); 3.15 (3H, s).

Biological Data

Inhibitory activity against human COX-1 and COX-2 was assessed in COScells which had been stably transfected with cDNA for human COX-1 andhuman COX-2. 24 Hours prior to experiment, COS cells were transferredfrom the 175 cm² flasks in which they were grown, onto 24-well cellculture plates using the following procedure. The incubation medium(Dulbecco's modified eagles medium (DMEM) supplemented withheat-inactivated foetal calf serum (10% v/v), penicillin (100 IU/ml),streptomycin (100 μg/ml) and geneticin (600 μg/ml)) was removed from aflask of confluent cells (1 flask at confluency contains approximately1×10⁷ cells). 10 ml of phosphate buffered saline (PBS) was added to theflask to wash the cells. Having discarded the PBS, cells were thenrinsed in 10 ml trypsin for 20 seconds, after which the trypsin wasremoved and the flask placed in an incubator (37°) for 1-2 minutes untilcells became detached from the flask. The flask was then removed fromthe incubator and cells resuspended in 10 ml of fresh incubation medium.The contents of the flask was transferred to a 250 ml sterile containerand the volume of incubation medium subsequently made up to 100 ml. 1 mlcell suspension was pipetted into each well of 4×24-well cell cultureplates. The plates were then placed in an incubator (37° C., 95% air/5%CO₂) overnight. If more than 1 flask of cells were required, the cellsfrom the individual flasks were combined before being dispensed into the24-well plates.

Following the overnight incubation, the incubation medium was completelyremoved from the 24-well cell culture plates and replaced with 250 μlfresh DMEM (37° C.). The test compounds were made up to 250× therequired test concentration in DMSO and were added to the wells in avolume of 1 μl. Plates were then mixed gently by swirling and thenplaced in an incubator for 1 hour (37° C., 95% air/5% CO₂). Followingthe incubation period, 10 μl of arachidonic acid (750 μM) was added toeach well to give a final arachidonic acid concentration of 30 μM.Plates were then incubated for a further 15 minutes, after which theincubation medium was removed from each well of the plates and stored at−20° C., prior to determination of prostaglandin E₂ (PGE2) levels usingenzyme immunoassay. The inhibitory potency of the test compound wasexpressed as an IC₅₀ value, which is defined as the concentration of thecompound required to inhibit the PGE2 release from the cells by 50%. Theselectivity ratio of inhibition of COX-1 versus COX-2 was calculated bycomparing respective IC₅₀ values.

The following IC₅₀ values for inhibition of COX-2 and COX-1 wereobtained for compounds of the invention: Example No. COX-2: IC₅₀(nM)COX-1: IC₅₀(nM) 1(v) 35 >100,000 2(ii) <10 3,880 3(ii) 3 >100,000 4(iii)370 >100,000 5 21 >100,000 6(iv) 0.44 3828 7(viii) 16 >55,200

1-13. (canceled)
 14. A pharmaceutical composition comprising a compoundof formula (I)

or a pharmaceutically acceptable salt, solvate, ester or salt or solvateof such ester, of a compound of formula (I) in which: R⁰ is halogen,C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one or more fluorineatoms, or O(CH₂)_(n)NR⁴R⁵; R¹ and R² are independently selected from H,C₁₋₆alkyl, C₁₋₆alkyl substituted by one or more fluorine atoms,C₁₋₆alkoxy, C₁₋₆hydroxyalkyl, SC₁₋₆alkyl, C(O)H, C(O)C₁₋₆alkyl,C₁₋₆alkylsulphonyl, C₁₋₆alkoxy substituted by one or more fluorineatoms, O(CH₂)_(n)CO₂C₁₋₆alkyl, O(CH₂)_(n)SC₁₋₆alkyl, (CH₂)_(n)NR⁴R⁵,(CH₂)_(n)SC₁₋₆alkyl or C(O)NR⁴R⁵; with the proviso that when R⁰ is atthe 4-position and is halogen, at least one of R¹ and R² isC₁₋₆alkylsulphonyl, C₁₋₆alkoxy substituted by one or more fluorineatoms, O(CH₂)_(n)CO₂C₁₋₆alkyl, O(CH₂)_(n)SC₁₋₆alkyl, (CH₂)_(n)NR⁴R⁵ or(CH₂)_(n)SC₁₋₆ alkyl, C(O)NR⁴R⁵; R³ is C₁₋₆alkyl or NH₂; R⁴ and R⁵ areindependently selected from H and C₁₋₆alkyl; and n is 1-4; and aninhibitor of the release, or action, of tumour necrosis factor α. 15.The pharmaceutical composition according to claim 14 further comprisingone or more physiologically acceptable carriers or excipients.
 16. Amethod of treating an animal subject suffering from a condition which ismediated by selective inhibition of COX-2, said method comprisingadministering to said subject an effective amount of the pharmaceuticalcomposition according to claim
 14. 17. The method according to claim 16,wherein said animal subject is a human.
 18. The method according toclaim 16, wherein said condition which is mediated by selectiveinhibition of COX-2 is selected from the group consisting of pain, feverand inflammation.
 19. The method according to claim 16, wherein saidcondition which is mediated by selective inhibition of COX-2 is selectedfrom the group consisting of rheumatic fever, influenza, cold, lowerback pain, neck pain, headache, toothache, sprains, strains, myositis,neuralgia, synovitis, arthritis, rheumatoid arthritis, degenerativejoint diseases, osteoarthristis, gout, ankylosing spondylitis,tendinitis, bursitis, psoriasis, eczema, burns, dermatitis, sportsinjuries, and injuries arising from surgical and dental procedures. 20.The method according to claim 16, wherein said condition which ismediated by selective inhibition of COX-2 is selected from the groupconsisting of colonic cancer, stroke, epilepsy, epileptic seizures,dysmenorrhoea, premature labour, asthma, allergic rhinitis, respiratorydistress syndrome, inflammatory bowel disease, Crohn's disease,gastritis, irritable bowel syndrome, ulcerative colitis, inflammation invascular disease, inflammation in migraine, inflammation inperiarteritis, inflammation in nodosa, inflammation in thyroiditis,inflammation in aplastic anemia, inflammation in Hodgkin's disease,inflammation in sclerodoma, inflammation in type 1 diabetes,inflammation in myasthenia gravis, inflammation in multiple sclerosis,inflammation in sorcoidosis, inflammation in nephrotic syndrome,inflammation in Bechet's syndrome, inflammation in polymyositis,inflammation in gingivitis, inflammation in conjunctivitis, inflammationin myocardial ischemia, retinitis, retinopathies, uveitis and acuteinjury to the eye.
 21. The method according to claim 16, wherein saidcondition which is mediated by selective inhibition of COX-2 is selectedfrom the group consisting of dementia, degenerative dementia, seniledementia, Alzheimer's disease, Pick's disease, Huntington's chorea,Parkinson's disease, Creutzfeldt-Jakob disease, vascular dementia,dementia associated with intracranial space occupying lesions, dementiaassociated with trauma, dementia associated with infections, dementiaassociated with HIV infections, dementia associated with metabolism,dementia associated with toxins, dementia associated with anoxia,dementia associated with vitamin deficiency, mild cognitive impairmentassociated with aging and Age Associated Memory Impairment.
 22. Themethod according to claim 16 wherein said condition which is mediated byselective inhibition of COX-2 is an inflammatory disorder.
 23. Themethod according to claim 16 wherein said condition which is mediated byselective inhibition of COX-2 is arthritis.
 24. The method according toclaim 16 wherein said condition which is mediated by selectiveinhibition of COX-2 is rheumatoid arthritis or osteoarthritis.
 25. Themethod according to claim 16 wherein said condition which is mediated byselective inhibition of COX-2 is inflammation in migraine.
 26. Themethod according to claim 16 wherein said condition which is mediated byselective inhibition of COX-2 is inflammation in multiple sclerosis. 27.A pharmaceutical composition comprising a compound selected from thegroup consisting of:3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-pyrazolo[1,5-b]pyridazine;6-difluoromethoxy-2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;2-(4-fluoro-phenyl)-6-methanesulfonyl-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;2-(4-difluoromethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;4-[2-(4-ethoxy-phenyl)-pyrazolo[1,5-b]pyridazin-3-yl]-benzenesulfonamide;and6-difluoromethoxy-2-(3-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;and pharmaceutically acceptable salts, solvates, esters and salts orsolvates of such esters, thereof and an inhibitor of the release, oraction, of tumour necrosis factor α.
 28. The pharmaceutical compositionaccording to claim 27 further comprising one or more physiologicallyacceptable carriers or excipients.
 29. The pharmaceutical compositionaccording to claim 27, wherein the compound is selected from the groupconsisting of2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;6-difluoromethoxy-2-(3-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;and pharmaceutically acceptable salts, solvates, esters and salts orsolvates of such ester, thereof.
 30. A method of treating an animalsubject suffering from a condition which is mediated by selectiveinhibition of COX-2, said method comprising administering to saidsubject an effective amount of the pharmaceutical composition accordingto claim
 29. 31. The method according to claim 30 wherein said conditionwhich is mediated by selective inhibition of COX-2 is an inflammatorydisorder.
 32. The method according to claim 30 wherein said conditionwhich is mediated by selective inhibition of COX-2 is arthritis.
 33. Themethod according to claim 30 wherein said condition which is mediated byselective inhibition of COX-2 is rheumatoid arthritis or osteoarthritis.34. The method according to claim 30 wherein said condition which ismediated by selective inhibition of COX-2 is inflammation in migraine.35. The method according to claim 30 wherein said condition which ismediated by selective inhibition of COX-2 is inflammation in multiplesclerosis.